This invention pertains to substituted 1,4,7-triazacyclononane-N,N′,N″-triacetic acid and 1,4,7,10-tetraazacyclcododecane-N,N′,N″,N′″-tetraacetic acid compounds with a pendant donor groups, conjugates and metal complexes thereof, compositions thereof and methods of using same.
Radioimmunotherapy (RIT), magnetic resonance imaging (MRI), positron emission tomography (PET), and iron depletion therapy (IDT) are promising techniques for targeted treatment or imaging of numerous diseases including cancers. The success of clinical applications of RIT, MRI, and PET depends heavily on the performance of a synthetic ligand that can bind either radioactive or non-radioactive metals which can be very toxic when deposited in normal tissues in vivo, causing life-threatening side effects.
RIT, an antibody-targeted radiation therapy, holds great promise for treatment of many diseases including cancers, evidenced by Zevalin® (1B4M-DTPA) therapy. However, active clinical exploration of RIT using a variety of antibodies and cytotoxic radionuclides has been challenged by the absence of adequate bifunctional ligands that can bind the radionuclides with clinically acceptable kinetics and in vivo stability. The currently available bifunctional ligands, C-DOTA and 1B4M-DTPA have limitations: C-DOTA forms a stable complex with metals but with clinically unacceptable slow complexation kinetics, while 1B4M-DTPA rapidly forms a less stable complex.

64Cu is proven to be effective for PET. Bifunctional ligands possess both binding moieties of Cu(II) and a functional group for conjugation to a targeting moiety are required for PET. Significant research effort has been made to develop 64Cu-based radiopharmaceuticals. However, less progress has been made on development of clinically viable bifunctional ligand to tightly and rapidly hold the short-lived metal.
MRI is a powerful diagnostic medical tool that provides non-invasive and high resolution imaging for a variety of applications. A number of Gd(III) complexes such as Gd(DOTA) are clinically approved for use in MRI. However, most contrast agents have non-specific extracellular distribution and the disadvantages of low relaxivity, low tissue specificity, and rapid clearance. Considerable research efforts have been directed toward developing safe Gd(III)-based MR contrast agents with high tissue specificity and sensitivity. Development of bifunctional ligands with a functional unit for conjugation to a targeting moiety that can tightly sequester Gd(III) is required for targeted MRI with high sensitivity and specificity.
The enhanced requirement of iron in cancer cells as compared to normal cells makes iron depletion using iron chelators targeting transferrin receptors or other proteins involved in iron uptake one of the most efficient strategies to prevent or suppress the rapid proliferation of cancerous cells. Iron chelators are reported to cause cellular iron depletion and exhibit potent cytotoxic activities on diverse cancer cells. Bifunctional iron chelator that can be linked to many peptides and monoclonal antibodies targeting to various types of tumor cells is a critical component to generate the antitumor conjugates for targeted iron depletion tumor therapy which has been little explored.
The invention provides such compounds. These and other objects and advantages, as well as additional inventive features, will be apparent from the description of the invention provided herein.